43,44 (2) Enhanced peroxisomal FAO, the first enzymatic step of which produces H2O2.5,45 (3) Higher mtFAO, which is also able to generate ROS, possibly at the level of electron transfer flavoprotein-ubiquinone oxidoreductase,46,47 or downstream within the MRC.5 Reduced ROS detoxification could also favor oxidative stress. Indeed, several studies showed lower GSH levels in NAFLD, including within the mitochondria.48-51 Decreased expression and/or activity of antioxidant

enzymes such as GPx and SODs could also occur, in particular at the mitochondrial level.48,52-55 NAFLD has been associated with higher hepatic expression of the inducible nitric oxide (NO) synthase (iNOS), mainly as a consequence of tumor necrosis factor-α

(TNF-α) overproduction by the Kupffer cells.56,57 Increased expression of the neuronal NOS (nNOS) could be also a significant source Raf inhibitor of RNS.58 NO can readily react with the superoxide anion, thus generating the RNS peroxynitrite, which has deleterious effects on mitochondrial function and genome.20,58 Genetic susceptibilities Acalabrutinib mw could increase the risk of developing fatty liver, but also its progression to NASH in some individuals. Thus far, a polymorphism in the adiponutrin (PNPLA3) gene seems to be the most robust genetic determinant associated with fatty liver.59 Genetic polymorphisms affecting the mitochondrial ability to oxidize fat could also modulate the risk of NAFLD, in particular in genes encoding PPARα, leptin, adiponectin, or receptors of these adipokines.5,59,60 Polymorphisms in the TNF-α, transforming growth factor-β, and MnSOD genes have been shown to favor NASH.5,59,61 During fatty liver, several metabolic adaptations can restrain fat accretion (Fig. 2). A major mechanism is the stimulation of mitochondrial and peroxisomal FAO.5,6,10,62,63 Increased mitochondrial oxidation of FAs and other substrates could also be an adaptation to produce more ATP needed for DNL and gluconeogenesis.64 However, higher FAO can be associated

with different mitochondrial abnormalities, as discussed below (Table 1). Another important adaptation in fatty Oxymatrine liver could be an increased release of VLDL.65-67 Thanks to different noninvasive methods, increased hepatic mtFAO was found in patients with fatty liver, or in obese individuals with prodromal features of the metabolic syndrome.68-70 Importantly, higher fat oxidation seems to persist in patients with NASH,42,71,72 as discussed later on (Table 1). In rodents, enhanced mtFAO was found in fatty liver induced by overfeeding,64,73-79 or by monosodium L-glutamate.53 Hepatic ketogenesis was also augmented in mice fed a high-fat diet (HFD),80 thus suggesting that higher acetyl-CoA generation by way of mtFAO is followed by efficient KB production. However, during severe IR, excess acetyl-CoA could also enter the TCA cycle, in particular to serve as a carbon source for gluconeogenesis.